Bispecific Antibodies (bsAbs): Mechanisms of Action Explained

I、Introduction

Bispecific antibodies (bsAbs) are engineered antibody molecules capable of simultaneously recognizing and binding two distinct antigens, or two different epitopes on the same antigen. Functioning as immune cell connectors, immune checkpoint modulators, or signaling pathway inhibitors, they have opened up new strategies for tumor targeting and immune modulation. Compared with conventional monoclonal antibodies, bsAbs integrate two antigen-binding specificities within a single molecule, thereby enabling novel mechanisms of action that go beyond the capabilities of natural antibodies.
图1 双特异性抗体三种作用机制.png

Figure 1. Three mechanisms of action of bispecific antibodies.

II、Core Mechanisms of Action: Redirection and Cooperative Engagement

bsAbs exert their effects primarily through two modes of action: combinatorial mechanisms and obligatory mechanisms.

Combinatorial mechanisms

The two binding sites of the bsAb act independently of one another. For example, amivantamab, which simultaneously blocks the EGFR and MET pathways, can circumvent resistance mechanisms mediated through the tyrosine kinase inhibitor (TKI)-binding site. Similarly, blocking receptor tyrosine kinases—as amivantamab does—or blocking immune checkpoints with cadonilimab can confer a therapeutic advantage by interfering with multiple tumor-promoting pathways, without requiring coordinated engagement of the targets.

Obligatory mechanisms

The biological activity of an obligatory bsAb strictly depends on the simultaneous engagement of both targets, which means that simply combining two monoclonal antibodies cannot replicate its function. T-cell engagers (TCEs) exemplify this mode of action: when one arm of the bsAb binds an antigen on the surface of a tumor cell while the other engages the CD3 complex on T cells, the molecule physically bridges T cells and tumor cells, bringing them into close proximity and promoting the formation of an immunological synapse. This bypasses the requirement for T-cell receptor (TCR) recognition of MHC–peptide complexes and directly activates the cytotoxic function of T cells.

III、Dual Pathway Blockade and Immunomodulation

Dual blockade of signaling pathways

In the treatment of solid tumors, bsAbs achieve synergistic antitumor effects by simultaneously blocking two tumor-associated signaling pathways. A representative example is amivantamab, in which one arm binds the extracellular domain of EGFR and the other blocks the MET receptor, effectively restraining tumor progression. Zenocutuzumab targets HER2 and HER3 and inhibits the growth of certain tumor types by blocking NRG1 fusion-driven HER2/HER3 heterodimerization.

Immunomodulatory effects

Dual targeting of immune checkpoints and pro-angiogenic factors: PD-(L)1/VEGF bispecific antibodies simultaneously block immunosuppressive signaling and tumor angiogenesis, synergistically reshaping the tumor microenvironment. As of 2026, several bsAbs, including ivonescimab, have been approved for the treatment of solid tumors.

T-cell engagers (TCEs): The introduction of TCEs represents a major breakthrough in immunotherapy, providing a new approach to activating T cells for the targeted destruction of cancer cells. As cancer immunotherapy continues to evolve, TCEs have delivered key innovations by harnessing the patient's own immune system to target and eliminate malignant cells. The approval of blinatumomab, a CD19/CD3-directed TCE, for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) fully demonstrated the clinical potential of this technology.

IV、Functional Engineering of the Fc Region

The design of the Fc region directly governs the in vivo behavior of a bsAb. For bsAbs that rely on T-cell engagement, mutations are typically introduced into the Fc region to abolish Fcγ receptor (FcγR) binding, thereby preventing nonspecific activation of immune cells and excessive cytokine release. Conversely, for bsAbs that depend on antibody-dependent cellular cytotoxicity (ADCC) effector function, Fc activity is retained or even enhanced. This fine-tuned molecular control is central to balancing the safety and efficacy of bsAbs.

V、Summary

Through independent dual-target blockade, bsAbs can effectively overcome the resistance that arises from inhibition of a single pathway. Acting as T-cell engagers, they forcibly bring immune effector cells into close contact with tumor cells, bypassing the restrictions of MHC presentation and creating new therapeutic opportunities for tumors of low immunogenicity. bsAbs have demonstrated tremendous potential in the treatment of solid tumors. Looking ahead, the molecular design of bsAbs will become increasingly precise and diversified, playing key roles across a broader range of tumor types as well as non-oncology indications. Nevertheless, further optimizing tumor selectivity, managing cytokine release syndrome, and exploring rational combination treatment strategies remain key challenges for future research.

Tek Biotech (Tianjin) Co., Ltd. has established a comprehensive, target-focused antibody drug discovery platform built on phage display and yeast display technologies. The company provides clients worldwide with high-quality discovery services for early-stage candidate sequences, together with a full suite of downstream services, including bispecific antibody design and preparation, in vitro validation (covering protein-level and cell-level binding assays as well as a variety of customized validation schemes), and in vivo efficacy evaluation (animal model studies and efficacy assessment). Through these one-stop services, Tek Biotech delivers robust technical support for clients' research programs.

References

[1] T cell engagers: expanding horizons in oncology and beyond. British Journal of Cancer, 2025.

[2] Bispecific Antibodies in Solid Tumors: Mechanistic Insights, Clinical Advances, and Future Directions. Journal of Immunotherapy and Precision Oncology, 2026.

[3] Prodrug-based bispecific antibodies for cancer therapy: advances and future directions. Frontiers in Immunology, 2025.

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